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REFERENCES 



1* Goodman, L* and Oilman, A* 1980s Pha mac o logic Basle of 
Therapeutics, editors of Sixth Edition; Kacmillan Pub. Co. t 
U.S.A. 

2. Brlmblecombe, R. W* 1974: Drug Actions on Cholinergic 
Systems. University Back Press, Baltimore* 

3. Veimer, K. neurotransmitter systems in the central nervous 
system* In Drugs and the Developing Brain* (Vernadakis, A- ( 
and Vainer, N., eds. ) Plenum Press, New York, 1974, pp. 
105-131. 

4* Rumack, B* H* 1973: Anticholinergic poisoning: treatment with 
phyaostlgfld.ae* Pediatries, 52, 449-451. 

5* Ketchum, J* S«; Sideil, F» R-; Crovell, E. G. 9 Jr.; Aghjanl&n, 
G* K«; and Hayes, A* H* t Jr. 1973: Atropine, Scopolamine, find 
Ditran: Comparative pharmacology and antagonists in man. 
Psycho pharmacologic, 28, 121*145. 

6* Shader, R* I*, and Greenblatt, D* J* 1972: Belladonna 

alkaloids and synthetic anticholinergics* Uses and toxicity. 
In, Psychiatric Complications of Medical Drugs. (Shader, R. I. t 
ed*) Raven Press, New York, 103-147. 

7. Forrar, G. R* and Killer, J* J. 1958: Atropine coma: a 

somatic therapy in psychiatry, Am. J, Psychiatry, 115, 45 5-45 B. 

8* Yamamura, H* I. and Snyder, S* H* 1974; Muscarinic 

Cholinergic Receptor Binding in the Longitudinal Muscle of the 
Guinea Pig Ilium with [3h] ' QuAnuclldlnyl Benzilate. Hoi. 
Pharmacol* 10 1 861-867* 

9* Hulas, E* C: Birdeall, N. J. M*; Burgen, A. S. V.; and Melsta, 
P- 1978: The binding of antagonists to brain muscarinic 
receptore. Hoi. Pharmacol. , 14, 737-750. 

10* Levins 9 R* M. 1959: The intestinal absorption of the 

quaternary derivatives of atropine and scopolamine. Arch. Int. 
Fharaacodym. Thar*, 121, 146-149* 

11« Jonkaam, J* H. 6*; Van Bork, L. E-; Wijsbeek, J.; De Zeeuv, R. 
A*; end 0rie t ■• G. If* 1977: Variations in the 
bioavailability of thlailnamium methy lsulfate- Clin. 
Pharmacol. Ther., 21, 457-463. 

12. Zvirblis, P# end Kondritser, A. 1966: adsorption of H 3 BZ 
and C^-a tropins to the mitochondrial fraction of the rat 
brain* Edgswood Arsenal Tech. Rept* 4042* 

; 
13* Sideil, F* R* undated: A summery of the 

investigations in man with BZ conducted by the U.S. Army, 
1960-1969* GSL 000-137* 

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14. Snyder, 5. H. p Chang, K* J- , luhar, M. J., Yaaaaura, H* I* 
1975s Biochemical Id ant if lea t Ion of Mammalian Muscarinic 
Cholinergics Receptor. Fad. Proc 34:1915-19;i. 

15. Yamemure, M. I. , Chang, K. J., Kuhar, M* J., Snyder, S. H. 
1975 s Cholinergic tftiecarinla Receptors Biochemical and Light 
Autoradiographic Localization In the Brain. Croat. Chea. 
Acta. 47:475^88. 

lb. Becker, M. J. 1964; Blochaalcal Studies of BZ and £A 3443. 
Final Report p Contract No. DA-18-104-GKL-6631. 









17. Ys manure, H* I. • Kuhar, H. J. » Greenberj? , D* B Snyder, S. H. 
1974 s Muscarinic Cholinergic Receptor Binding: Regional 
Distribution in Hookey Brain. Brain Rea. 66:541-546* 






18. Eetchum, J. 1963; The human assessment of BZ. Chemical 
Research and Development Laboratories Tech- Meuo 20^29. 

19. Lowy, K ft Abood, Lt C and Raines, fi* : 1976. behavioral effects 
and binding affinities of two star* oieome trie psychotomimetic 
glycolatee. J. Heuroeci, Res. 2, 157-165. 

20- Abood, L.G. and Rlnaldi, F.s 1959. Studies with a tritium 
labeled paychotoaiaatlc agent* Psycho Pharmacol. 1:119-123. 

21. Shall**, V. and Smith, T. H. F* 1952; Electrcencephalogrsphic 
analysis of side effects of spasmolytic drugs- J* Pharmacol. 

Exp. therap. 104:291-298. 






22. McNamara, B. F. i960; Research in Toxicology Division on 
Effects of CS4Q30 id animals. Chemical Warfare Laboratories 
Special Pub. 2-28. 

23* Mannaar, J., Samuel, G. , Jennings, B, McCarthy D. B OH, J., 
Marshall, E. and Sbith, B. Preclinical Pharmacology Study - 
Monkeys (EA3443). Contract DA 18~108-AHC-78[A] (C73, Index 
105). 

24. Mannaar, J*, Jennings, H* , Kuldell, K», Hall, D. , Poland, R. and 
Leah, R* Fracllnlcal Pharmacology Study - Dogs. Contract 
DA-18-108-405-CML-826. 

25. Shiner , P. T. f Mej., H. C. , Agent EA3B34-renal evaluation as of 
Jan. 1970, Clinic Investigation Branch, Clinical Medical 
Sciences &spt. f Mad. las* Labs. 

26. Boyd, C E. and Boyd, E. M. 1962. The chronic toxicity of 
atropine administered intramuscularly to rabbltti. Tox. Appl. 

Phara. 4:457-467. 

27. Bagdon, R.E., 1965; One year chronic toxicity utudlee of 
quartxan in dogs, Dec. 13, 1965* Hoffaaon-LaRoche, Inc. 
(Prepared by Food and Drug Ras. Labs. Inc. and submitted to 
Hoffmann LaRoche Dec. 8, 1965 for use In connection with nev 
drug application to FDA for human use) . 

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28* Bagdon, E.E. and Garner, I., 1966 J One year chronic toxicity 

etudlee of clldiaium bromide in rat*. April 20. 
Hof fmantHLaBo cha t lac* 

29- Ctnon, S. 1965i Chronic (1-yeer) oral dotage studies with 
Quartzan In doge* Report from Food and Drug Research Labs., 
Inc. to Hoffmann LaRochm, luc* 



■ 



30* 5ru, R. J., Kucerove, M* and Bardode, Z. 1975: Mutagenic 
Activity of 3^hi Que lidylbenzi late. 

I 

31. Crovmll, E. B. t Jr., and Eat chum J* S. 1967: The treatme&t of 
icopolamiae -induced delirium with phyaoatlgmine* Edge wood 
Arsenal Itch. Bept, 4115. 






32* Clapper, A. J.» HcCenoll, J* I. end HcColloch, M. 1972: 

Long-term follovup of medical volunteer*. Edgewood Arsenal 
Tech. Rapt* 4611* 



. 



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33* Hart, J.J. and Baiter, L*3 1966. A atudy of poaalble residual 
EFFE GTS of EA 3443 and EA 3580 on COG Ni:lve Ability [U]. 
Aberdeen Proving Ground, Maryland* 



. 



34* Abood, L.G* and Heduna, L*J*s 1958* Sams effecte of a new 
payefcotogen in depre salve etatea. J. Nerv. Kent. Die 127, 
546-554* 

35* Medusa, L* J* and Abood, L. G« J* Neuropeych. 1:20-22, 1959. 
"Studiee of a New Drug (Ditran) in Depressive States." 

36. Flnkelatalit, B. A.; 1961. filtran, a psychotherapeutic 
advance: & review of 103 cases. J* Neuropsychiat, 2, 144-148 

37. English, D* C* ; 1962. lalntegration of affect and psychic 
emergence with Ditran. J, Heuropeychlat. 3. 304-310. 



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4 
MOBIALITX 

- 

METHOD OP ANALYSIS 

^ ^ ^ ■ 

The testing of chemical agents in human subjects at Edgevood 
vhlch began in 1955 continued for more than 20 yr. During that 
period , the volunteers participated in an average of 3.1 tests each; 
2 92 participated in only one teat! and 2% participated in 10 or more 
teats. Because most of the volunteers participated in mote than one 
test, the date of the most recent test was arbitrarily set as the 
date on which followup by the Medical Follpwup Agency of the 
National Research Council and the ascertainment of mortality began* 
Follovup continued through December 31 , 19SQ* The period of 
followup ranged' from 4 to a laaxinmra of 26 completed years. 

The experience of 6,620 men is examined .here* One-hundred were 
excluded from the study because of erroneous identification or 
because some essential datum t such as date of birth , was unknown. 
Among those studied, there were 222 deaths. 

Deaths during follovup were identified by matching the 
volunteers against a computerized file of veterans maintained by the 
Veterans' Administration (VA), which Includes the date of death of 

■a -" 

every veteran for whom the VA has received a claim for a burial 
allowance and other veteran death benefits. Both name and service 
number were used for matching* If a death certificate shoving the 
cause of death could not be found Id the VA claim folder for a 
deceased veteran, a copy of the certificate was requested from the 
vital statistics office of the jurisdiction where the death 
occurred* The underlying cause of death vas coded for analysis* 
The 31 deaths for which death certificates had not been received by 
the cutoff date for the receipt of data for ana lysis --March 31, 
1982 — have been classified as "cause of death unknown." These 11 
deaths are distributed In similar proportions between the men who 
received potentially hazardous substances (15% of 134 deaths) and 
the men who did not (131 of 86 deaths). 

The groups of volunteers cannot be compared for mortality solely 
on the basis of numbers of observed deaths. One must also take into 
account the number of years that each group has been followed and 
the ages of the men being observed. The volunteers in the early 
test years were about the same age as men used in tests conducted 
during the later years (Table 4-1). However, the men tested in the 
early years not only are under observation for a much longer period 
than men used in the most recent tests » but also have grown older 
and have had a longer followup. Consider two volunteers of the same 
age at testing, one whose followup began In 195S and the other in 
1970* The first man will have aged 15 yr by the time the second man 
Is tested and will have been exposed to the risk of dying for an 
additional 15 yr at the end of follovup. Thus, the proportion of 
volunteers who die during followup will decrease for esch succeeding 
test group t in the absence of any drug effect. 

The testing of drugs spanned a period of 21 yr. However, some 
chemical agents were tested earlier than others (Table 4-2)* The 
testing of LSD and derivatives was concentrated in the early years; 
more than half the total number of doses had been administered by 



77 



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the end of 1959* At the other extreme were the approved drug* 
innocuous substances, and control substances, which were 
administered late in the testing period* One can therefore expect a 
much higher proportion of men in the LSD tests to have died than of 
the men who received approved drugs, innocaouu chemicals, or control 
substances, even if LSD and its derivatives have no adverse effects 
on survival. 

If one calculated the numbers of deaths expected among a test 
group of men, on the basis of their ages and the numbers of years 
they were followed , one would have a yardstick for assessing the 
significance of the number of deaths observed during followup. The 
ratio of observed deaths to expected deaths, the standardized 
mortality ratio (SHE) t can be used to compare the mortality 



experiences o+ two or sore groups* ucpecteu ueatiis ^y uudcrlyliig 
cause were calculated on the assumption that the volunteers 
experienced U.S. male, age-specific death rates for each calendar 
year of followup* 

RESULTS 

Because most of the volunteers participated in two or more 
tests, an analytic problem arises: If one of the test substances, 
say Substance A, produced detectable adverse effects, such effects 
would also tend to appear among men who received Substance B if 
there were many men tested with both substances k and B. 
Accordingly, data on men who were tested with any particular 
substance are shown in two nonover lapping groups: those who received 
"only* that substance (whether once or more than once) and those who 
received "not only" that substance but other active substances as 
well* 

Observed and expected numbers of deaths and the ratios of 
observed to expected deaths, the SHRs, by underlying cause of death 
in volunteers who were exposed to chemicals of various types, are 
shown In Table 4-3- As noted above! a distinction has been made 
between men who received only one type of chemical and those who 
were exposed to two 'or more types (the "not only" groups) - 

The SHE for the total experience, 0.81 p indicates that observed 
mortality for all causes was -only 81Z of expectation* That reflects 
the requirement that a man meet minimal health standards to be 
accepted into the Army; the screening process results in a death 
rate that la lower than that of U*S« males in general, and this 
effect persists for many years* It Is evident that men who were 
tested with active) substances had been subjected to additional 
Screening, So these men constituted an unusually fit group and might 
be expected to have unusually low mortality for a number of years. 
This phenomenon Is Identical with the "healthy-worker" effect that 
is seen In most studies of occupational group* Ken who were exposed 
to two or more types of chemicals experienced lower SM&s than those 
exposed to only one type of compound, again because of selection, a 









multiple teats* 

Mo "ill causes" SHE exceeded 1 by an amount greater than can 

reasonably be attributed to chance* The high SHR, 1.11, 
representing sn 111 excess of observed deaths, occurred in the "no 
test" group—men who were not exposed to any chemical agent, 



78 






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possibly because of some health defect detected in the examination 
that preceded testing. The highest SHE, 1.20, occurred la the email 
group of men exposed only to the cholinestaraee react i /a tors and 
represents id excess over expectation of leas than a single death. 

The only other SMR to exceed unity occurred In aen who were exposed 
to the anticholinergic chemical* only. Hen vho were exposed co 
anticholinergic chemicals plus other chemicals (which sometime a 
included substances to counteract the effects of the anticholinergic 
chemicals) had an SMR* 0. 56 , which la significantly below unity. 
However 4 when 212 aen exposed to low single doses and 319 to high 
single doses were examined separately , no dose effect was apparent. 

Bad the anticholinergic chemicals increased the risk of dying, one 
would have expected that increase to be larger In men with larger 
■ingle exposure a* 

No evidence of a deferred, drug-induced mortality increase was 
seen when the experiences of the first 10 and remaining 16 follow-up 
years were examined separately. Of the 14 categories of 
experimental chemicals studied, only two had an SMR exceeding unity 
during the last 16 follow-up years* One of these (cholinest erase 
reactivator, only) was clearly due to small numbers, one observed 
death with 0*8 deaths expected, while the other t 47 observed versus 
39.7 expected deaths, was seen in the 1,719 volunteers who were not 
exposed to any of the chemicals, the "no teat" group* We can state 
with 95-percent certainty that the true SMR for these men during the 
first 10 years fails between 0*69 and 1.36, while the limits for the 
last 16 years are 0*83 and 1*54, respectively* 

Host of the experimental chemicals were administered to too few 
volunteers to he examined separately for an influence on mortality. 
However, a few were considered of sufficient interest to justify 
being examined in that way (Table 4—4)* The specific chemicals are 
grouped by type. The SMEs for these Individual compounds range from 
a low of 0*80 (nine observed, 11.3 expected deaths) for the men 
tested with sarin only, to a high of 2.50 (five observed, two 
expected) for scopolamine only* Atropine, a therapeutic 
anticholinergic similar to scopolamine, had the next highest SMR, 

1*76 (three observed, 1.7 'expected)* Of the eight deaths of men who 
received one or the other of these two therapeutically similar 
compounds, three were attributed to trauma (one accident, one 
suicide, and one other trauma) , and one was due to cancer; the 
causes of the other four will not be known until the death 
certificates are obtained* 

The SMEs become much more erratic when attention is directed to 
the underlying causes of death, because of the small expected 
number* If 0.5 deaths are expected , the SMR will be 0.0, 2.0, or 
4*0, if only aero, one, or two deaths are observed. 

Trauma was the underlying cauae of 86 deaths, compared with 
128.2 expected, for an SMR of 0.67* These volunteers had a 
significantly lower death rate from injury than that experienced by 
U.S. males In general* Thia tendency la seen in every category of 
test chemical, with two exceptions — the S70 men who received 
anticholinergic agents only (10 observed, 10*0 expected, SMR - 1*00) 
and the 607 men who received choline a teraae reactivators (11 
observed, 11*0 expected, SMR - 100)* In each instance, deaths due 
to homicide contributed to the excess. It would be difficult to 
attribute an increase in deaths due to trauma to effects of the two 
types of chemicals f because the excess is not seen among all 



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• 



volunteer* expoeed Co them* No excess It seen in the 
anticholinergic "not only" group or in the chollnesterase 
reactivator "only" group. 

Three diseases were responsible for nore deaths then expected 

among all volunteers; cancer of the respiratory tract, leukemia and 
a leukemia, and renal disease. All three renal-disease deaths vera 
in the no-teat group; the excess ia clearly not a drug effect. The 
excess of respiratory-cancer deatha derive* in part froai the control 
and no-tee t groups; that suggest e that the excees is general, not 
drug-related. Deatha due to respiratory cancer vere responsible for 
an SHI of 1.11 In a group of World War II and Korean Conflict 
veterans (1). It is possible that the proportion of 
cigarette-mmokara ia higher among vateraae than in the U.S. male 
population in general* The third disease causing more deatha than 
expected ia leukemia and aleukamia (four observed , 2.8 expected, SHR 
■ 1.43)* One death occurred in the iDnocuoua-cheaical and-control 
group. Of the other three who died of leukemia or aleukemia, tvo 
bad received anticholinesterase ageate, two chollnesterase 
reactivators, and one each irritants, cannabis, and an unclassified 

chemical (included under total emparlance in Table 4-3), When the 
total volunteer experience ie divided into the 1,984 men who did not 
receive potentially hazardous chemicals and the 4,636 men vho did, 
the average annual death rates from leukemia are similar— 3.4 and 

4.0 per 100,000 pereon-yr of observation, respectively. 

What ia the chance that an increased risk of death will actually 
be detected? after choosing a level of significance at which the 
null hypothesis (no increased rlak) will be rejected (P .OS, say), 
the power of a compariaon ia the probability that, in fact, the 
number of deatha observed will ba large enough to constitute a 
significant ezceea ovar the number expected if there were no 
increased rlak* 

Power can be large if the relative rlek ia large or if the 

sample is sufficiently large. If the sample la small, then only 

fairly large relative risks trill be detected with high probability. 
In particular, if 10 or mora deatha would be expected on the null 

hypothesis, a relative risk of 2.0 would be detected in more than 80 
percent of trials (power greater than 0*80} - The same power ia 
achieved if three deatha arm expected only if the relative risk le 
at least 3*0, and if only two deatha are expected at U.S. population 
rates, the relative rlgk would have to be at least 4.0 to achieve a 
power of 0.80. Whan tha number of man exposed to a given chemical 
are email enough or the condition at increased risk rare enough to 
produce an axpected value of only 0.1 deaths, failure to demonstrate 
a significant Increase would mean only that the relative risk le 
less than 30* From a atatistical point of view, the experience 
being studied ia Incapable of demonstrating risks of dying increased 
leas than three- or four-fold* 

It can ba concluded that, over the tine span examined here, 
there ia no evidence that volunteer participation In the teating 
programs had any long-term adverse effect on mortality. 



80 



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Table 1 






Number ■ of Men Tetted by Year of Birth 
end Year of Beginning of Followup 



1 



Year of Birth 


1955- 

1959 


1960- 
1964 ' 


, 1965- 
1969 




No. Mem: 






Before 1920 


35 


17 




1920-1924 


55 


22 


2 


1925-1929 


118 


78 


I 


1930-1934 


417 


139 


17 


1935-1939 


491 


837 


77 


1940-1944 


47 


978 


805 


1945-1949 




31 


1,191 


1950-1954 






18 



19 70 



After 




1 



11 



69 



571 



516 



70 



Total 



52 



79 



197 



573 



1,422 
1,899 



1.793 



534 



71 



Total 



1,163 



2,102 



Keen Year of Birth: 



2,112 



1,243 



6,620 



1934 



1939 



1945 



1950 



1942 



Mean Age at Beginning of Followup, yr 



23.9 



23.5 



22.4 



21.8 



23.1 



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T*bU 2 



Median Yean in Which Categories of 
Chemicals were Adminii tared 



Gate 




Anticholinesterases 



Irritants 
Cannabis 

liSB derivative! 

Approved drugs 






Innocuous chemical ■ and controls 



, 



■ 






■ 



82 



Year 



1962 



Anticholinergic* 196a 

Cholineaterase reactivat 



° r « 19 6S 



1967 



1965 



1959 



1971 



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Observed and Expected n-,*k- 



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Kemiinder 



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REFERENC E 

Ke»hn, ft, J, t 1980: Follow-up Studies 
Conflict Prisoner*, III. Hortality to 
Epidemiol. 111:194-211. 



of World War II 
1 January 1976, 



and 
Am * 



Ko 
J. 



n 












87